1. Field of the Invention
This invention concerns the use of synthetic Lipid A analog P9132 to activate human monocytes. Activation of monocytes is useful in the stimulation of immune responses in the treatment of various diseases.
The Lipopolysaccharides (LPS) are a group of diverse lipid containing carbohydrates that exhibit a wide variety of biological activities. They occur naturally on the outer cell membranes of gram negative bacteria such as Salmonella minnesota, Salmonella typhimurium and Escherichia coli. Although the lipopolysaccharides are large molecules, most of their biological activities result from the activity of a small portion of the molecule known as Lipid A. The structure of Lipid A consists of two .beta.(1,6)-linked D-glucosamine units with polar phosphate groups at 1 and 4' positions. The 2 and 2' amino positions and the 3 and 3' hydroxyl group are esterified with hydroxy fatty acids. It is known that natural Lipid A compounds are potent immunostimulants which cause various desirable effects but also some undesirable ones. Various synthetic analogues of Lipid A have been developed to avoid such undesirable effects as toxicity and pyrogenicity. The P9132 analog of Lipid A of the present invention has been found to stimulate the human monocyte to produce interleukin-1 (IL-1) and several other substances produced by activated monocytes and to inhibit the growth of tumor cells in mice. Because of its ability to activate monocytes and stimulate the production of IL-1 and TNF and because it is relatively non-toxic, P9132 may be useful in cancer therapy and to stimulate suppressed immune systems.
2. Background Art
Various Lipid A analogs have been synthesized.
Kiso et al., Carbohydrate Research, 162 (1987) 247-256, describe the synthesis of two types of optically active 4-O-phospho-D-glucosamine derivatives related to the non-reducing sugar subunit of bacterial Lipid A.
Tadayori Shimizu et al., Antitumor Activity and Biological Effects of Chemically Synthesized Monosaccharide Analogues of Lipid A in Mice, Chem. Pharm. Bull., 3, 10 (1985) 4621 et seq. synthesized five monosaccharide analogs of Lipid A and tested these against the ascites form of Ehrlich carcinoma and investigated their toxicity in mice.
International application PCT publication WO84/04526 teaches novel compounds which stimulate the immune cells in animals in a manner similar to Lipid A.
U.S. Pat. No. 4,719,202 discloses disaccharide and trisaccharide derivatives of Lipid A having immuno-modulating properties. EP 172,581 describes the use of a Lipid A type disaccharide derivative for inducing mutagenic and tumor necrosis factor activities in a murine system. EP 143,840 describes the use of a monosaccharide Lipid A analog as an immunostimulant.